Chronic immune thrombocytopenic purpura
Immune Thrombocytopenic Purpura

Author: Giuseppina Amato
Date: 20/05/2012



Idiopathic (or autoimmune) thrombocytopenic purpura (ITP) is an acquired disorder characterized by mild to severe thrombocytopenia, a relatively normal appearing bone marrow, and mucocutaneous bleeding.
Visible symptoms of ITP include the spontaneous formation of bruises (purpura) and petechiae (tiny bruises), especially on the extremities, bleeding from the nostrils, bleeding at the gums, and menorrhagia (excessive menstrual bleeding), any of which may occur if the platelet count is below 20,000 per μl. A very low count (<10,000 per μl) may result in the spontaneous formation of hematomas (blood masses) in the mouth or on other mucous membranes. Bleeding time from minor lacerations or abrasions is usually prolonged.


The triggering event for ITP is unknown, but continued research is providing new insights into the underlying immunopathogenic processes as well as the cellular and molecular mechanisms involved in megakaryocytopoiesis and platelet turnover.
Platelet membrane proteins, for reasons that are unclear, become antigenic and stimulate the immune system to produce autoantibodies and cytotoxic T cells. The initial antigenic response probably occurs in the spleen followed by stimulation of other antibody-producing tissues, particularly the bone marrow. Autoantibodies against platelet glycoprotein (GP) IIb-IIIa and/or GPIb-IX are produced by the majority of ITP patients (McMillan et al) and can be detected using antigen-specific assays.

Autoantibody may either bind to platelets, causing their destruction by either phagocytosis or possibly complement activation and lysis, or bind to megakaryocytes, resulting in decreased thrombopoiesis.

Mechanisms underlying idiopathic thrombocytopenic purpura

- Autoimmune mechanisms:

  • Antiplatelet antibody secretion by autoreactive B lymphocytes
  • Dysfunctional cellular immunity (autoreactive T cells)
  • T cell–mediated cytotoxicity
  • Natural killer cell activation

- Impaired thrombopoiesis:

  • Autoantibody suppression of megakaryopoiesis and thrombopoiesis
  • Thrombopoietin dysregulation

McMillan et al. reported that IgG produced by cells (grown in vitro) from the spleens of patients with ITP would bind to megakaryocytes, whereas IgG produced by cells from the spleens of healthy controls did not bind to megakaryocytes.
A few years later other investigators demonstrated that antibodies against platelet antigens would bind to megakaryocytes as well (Rabellino et al.). More recent in vitro experiments have further defined the role of autoantibodies in patients with ITP. Two studies in particular (Chang et al. and McMillan et al.) support the view that autoantibodies in ITP suppress megakaryocyte production and maturation and platelet release.

Drug-induced thrombocytopenia

Drugs are a common cause of acute immune-mediated thrombocytopenia in adults.
Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependent antibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions but only in the presence of the drug.
It has been proposed that the sensitizing drugs typically contain charged and/or hydrophobic structural elements that enable them to bind to both the antibody and platelet surface proteins. In this model, the drugs bind noncovalently and reversibly to platelets, commonly to sites on GP IIb-IIIa and/or GP Ib-V-IX, and also to the antibody. The resulting “sandwich” facilitates formation of a tight bond between the antibody and the platelet epitope.
Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenly after a single dose when a drug has previously been taken intermittently. However, severe thrombocytopenia can occur immediately after the first administration of antithrombotic agents that block fibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week. Drugdependent antibodies can persist for many years; therefore, it is important that the drug etiology be confirmed and the drug be avoided thereafter.
(Drug-induced thrombocytopenia: pathogenesis, evaluation, and management)

Immune Thrombocytopenic Purpura due to Viral Infections

Persistent thrombocytopenia may be the consequence of chronic infections with hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Helicobacter pylori, and should be considered in the differential diagnosis of primary immune thrombocytopenia (ITP). Studies have shown that on diagnosis of infections, treatment of the primary disease often results in substantial improvement or complete recovery of the thrombocytopenia. In patients with thrombocytopenia due to HCV-related chronic liver disease, the use of eltrombopag, a thrombopoietin receptor agonist, normalizes platelet levels, thereby permitting the initiation of antiviral therapy. Antiviral therapy with highly active antiretroviral therapy for HIV has aided in platelet recovery, with a corresponding decrease in circulating viral load. Thrombocytopenia in the absence of other disease symptoms requires screening for H. pylori, especially in countries such as Japan, where there is a high prevalence of the disease and the chances of a platelet response to eradication therapy are high.
(Infectious causes of chronic immune thrombocytopenia)

Therapies target platlet production

The currently available treatment for ITP targets the autoimmune response and platelet destruction. Various treatment options, such as corticosteroids, androgens, cytotoxic chemotherapy, rituximab, immunosuppressive agents, and immunoglobulin preparations, are directed against different steps and phases of the immune response.
(Chronic Idiopathic Thrombocytopenic Purpura:Mechanisms of Pathogenes)

ELTROMBOPAG is one of a number of novel agents recently developed for use in the treatment of patients with immune thrombocytopenia (ITP).
(Cook at al.)

Estrogen effects on autoimmune disorders

An effect of estrogens on macrophage Fc (IgG) receptor-mediated clearance may explain in part the variation in clinical expression of several autoimmune disorders during changes in hormonal state, such as pregnancy.
(Friedman et al.)

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